Depletion of Neural Crest–Derived Cells Leads to Reduction in Plasma Noradrenaline and Alters B Lymphopoiesis

Abstract

Hematopoietic stem cells and their lymphoid progenitors are supported by the bone marrow (BM) microenvironmental niches composed of various stromal cells and Schwann cells and sympathetic nerve fibers. Although neural crest (NC) cells contribute to the development of all the three, their function in BM is not well understood. In this study, NC-derived cells were ablated with diphtheria toxin in double-transgenic mice expressing NC-specific Cre and Cre-driven diphtheria toxin receptor with yellow fluorescent protein reporter. We found that yellow fluorescent protein-expressing, NC-derived nonhematopoietic cells in BM expressed hematopoietic factors Cxcl12 and stem cell factor The ablation of NC-derived cells led to a significant decrease in B cell progenitors but not in hematopoietic stem cells or myeloid lineage cells in BM. Interestingly, plasma noradrenaline was markedly decreased in these mice. The i.p. administration of 6-hydroxydopamine, a known neurotoxin for noradrenergic neurons, led to a similar phenotype, whereas the administration of a noradrenaline precursor in NC-ablated mice partially rescued this phenotype. Additionally, the continuous administration of adrenergic receptor β antagonists partially decreased the number of B cell progenitors while preserving B lymphopoiesis in vitro. Taken together, our results indicate that NC-derived cell depletion leads to abnormal B lymphopoiesis partially through decreased plasma noradrenaline, suggesting this as a novel mechanism regulated by molecules released by the sympathetic neurons.

Nociceptive nerves regulate haematopoietic stem cell mobilization

“…To distinguish between these possibilities, we treated wild-type C57BL/6 mice systemically with either vehicle, resiniferatoxin (RTX), 6-hydroxydopamine (6OHDA), or both to differentially ablate nociceptive or sympathetic nerve fibres, respectively ( Extended Data Fig.1c - e ). While sympathetic denervation significantly suppressed B lymphopoiesis—in line with previous studies 11 , neither sympathetic nor sensory denervation alone altered HSC numbers in the BM ( Extended Data Fig.2a - d ). However, the dual denervation induced significant HSC expansion and led to a myeloid bias of haematopoiesis ( Extended Data Fig.2c , d ).…”

β2-adrenergic signals downregulate the innate immune response and reduce host resistance to viral infection

“…5 D). 6-OHDA treatment is used to selectively target noradrenergic neurons without affecting the adrenal medulla or plasma adrenaline levels (Clark et al, 1972;Tsunokuma et al, 2017). As expected, 6-OHDA treatment induced the ablation of tyrosine hydroxylase (TH) + sympathetic fibers in both the spleen and the liver (Fig.…”

Niches for Hematopoietic Stem Cells and Their Progeny

“…Notably, other cell types, such as adipocytes (Bilwani and Knight, 2012), Treg (Kim et al, 2015), monocytic cells (Day et al, 2015), or long-range signals such as sex steroids (Dudakov et al, 2009) and nerves (Katayama and Frenette, 2003, Tsunokuma et al, 2017), could also directly or indirectly regulate lymphoid progenitors (Figure 2). A correlation between B lymphopoiesis and osteoclast abnormalities was also suggested by several studies of the TNF pathway components (Manabe et al, 2001, Kong et al, 1999, Franzoso et al, 1997).…”